Nikhil Wagle, MD, Dana-Farber Cancer Institute, Boston, MA, outlines mechanisms of resistance to endocrine therapies in estrogen receptor-positive (ER+) metastatic breast cancer, such as alterations in the estrogen receptor, alternative pathway activation and subtype alteration. Dr Wagle describes how different approaches are required to treat patients with different mechanisms of resistance. This interview took place at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.